Internalization of the interleukin 6 signal transducer gp130 does not require activation of the Jak/STAT pathway.
Signalling receptors often undergo receptor-mediated endocytosis. In many cases this internalization is stimulated by ligand binding and activation of intrinsic receptor tyrosine kinases, resulting in a receptor down-regulation. We have analysed whether internalization of the interleukin 6 signal transducer gp130 is dependent on the activation of receptor-associated Jak kinases. By using a chimaeric receptor system we found that receptor mutants that lack box1 and therefore are not capable of activating Jak and signal transducer and activator of transcription (STAT) proteins are still endocytosed efficiently. A chimaeric receptor with the recently identified dileucine internalization motif being replaced by two alanine residues was not efficiently internalized but still capable of recruiting STATs. Furthermore an antagonistic antibody that inhibits the signalling of all interleukin-6-type cytokines via gp130 was internalized as efficiently as an agonistic one that activates the Jak/STAT pathway. Our findings suggest that the endocytosis of gp130 is signal-independent.
Thiel
S
S
Institute of Biochemistry, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse 30, 52057 Aachen, Federal Republic of Germany.
Behrmann
I
I
Dittrich
E
E
Muys
L
L
Tavernier
J
J
Wijdenes
J
J
Heinrich
P C
PC
Graeve
L
L
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D019556:COS Cells; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004705:Endocytosis; D015848:Interleukin-5 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism; D053649:Receptors, Interleukin-5; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D011505:Protein-Tyrosine Kinases